The integrity of the cartilage surface and its surrounding synovium affects the homeostasis and long-term function of an articulating joint. This is a competitive renewal application to continue our studies of the secreted protein lubricin (encoded by the gene PRG4), which is expressed by superficial zone chondrocytes and type B synoviocytes. We and other investigators have shown that lubricin is critically important in the protection and maintenance of articulating joints. We have demonstrated that lubricin prevents mechanical wear of articular cartilage. Humans and mice that genetically lack lubricin develop precocious cartilage failure and synovial hyperplasia. We have observed acquired alterations of lubricin in patients with common joint diseases, including osteoarthritis, rheumatoid arthritis, and traumatic joint injury. These acquired alterations of lubricin can include changes in protein abundance, the expression of different protein splice-forms, and specific post-translational processing events, such as glycosylation and protein cleavage, which appear to be important to the protein's biological and mechanical activities. We have three overall research goals. First, we want to understand precisely how the different lubricin splice-forms and post-translational modifications contribute to the protein's diverse cell biologic, structural, and biophysical properties. We will accomplish this by studying protein and tissue recovered from wild-type animals, lubricin-mutant animals, and transgenic mice that express specific lubricin splice-forms or lubricin proteins that have been mutated to prevent normal post-translational processing. In aim two we will develop a reliable and reproducible methodology for inducing and measuring wear in whole joints. This will enable us to understand how lubricin prevents wear in vivo. It is important to appreciate that not all good lubricants prevent wear. Therefore, we want to precisely define how lubricin prevents wear and which of its post-translational modifications are important to this activity. Third, we want to correlate acquired alterations of lubricin with common diseases of joints and determine whether these lubricin alterations are causes or consequences. We will do this by analyzing synovial fluid and serum from cohorts of patients affected by common joint diseases and from animal models of acquired joint disease, such as traumatic joint injury and inflammatory arthritis. PUBLIC HEALTH RELEVANCE. This research aims to understand how the secreted protein lubricin protects mammalian joints. Genetic absence of lubricin cause precocious joint failure. Our preliminary data suggest that acquired alterations of lubricin contribute to the progression of joint disease in patients with more common diseases affecting joints, such as osteoarthritis, rheumatoid arthritis, and traumatic joint injury. We will study mice that express different forms of lubricin and also study biologic samples from patients with normal and damaged joints to begin correlating lubricin variation with human joint health.